An efficient microwave-assisted solvent-free synthesis of pyrido-fused ring systems applying the tert-amino effect

Article abstract of DOI:10.1016/j.tet.2005.07.046

Significant improvements in the synthesis of pyrido-fused heterocycles were observed when performing the reaction under solvent-free conditions, applying the tert-amino effect as the key ring closure methodology. An unexpected cyclization of ortho-(1′-aza

Full text of DOI:10.1016/j.tet.2005.07.046

Tetrahedron 61 (2005) 9052–9057
An efficient microwave-assisted solvent-free synthesis
of pyrido-fused ring systems applying the tert-amino effect
Nadya Kaval,a Beata Halasz-Dajka,b Giang Vo-Thanh,c Wim Dehaen,a Johan Van der Eycken,d
b
Peter Matyus, Andre Loupy and Erik Van der Eycken
c
a,
*
´
´
´
aDepartment of Chemistry, Catholic University of Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
b
˝
Department of Organic Chemistry, Semmelweis University, Hogyes u. 7, Budapest, Hungary
´ ´ ´
Laboratoire des Reactions Selectives sur Supports, CNRS UMR 8615, Universite Paris-Sud, ICMMO,
c
ˆ
batiment 410, 91405 Orsay Cedex, France
dLaboratory for Organic and Bio-organic Synthesis, Gent University, Krijgslaan 281, B-9000 Gent, Belgium
Received 17 May 2005; revised 12 July 2005; accepted 14 July 2005
Available online 3 August 2005
Abstract—Significant improvements in the synthesis of pyrido-fused heterocycles were observed when performing the reaction under
solvent-free conditions, applying the tert-amino effect as the key ring closure methodology. An unexpected cyclization of ortho-(10-aza-
cycloalkyl)benzaldehydes has been studied in water and on solid support.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
solvent-free synthesis of pharmacologically interesting
pyrido-fused ring systems under both MW irradiation and
conventional heating conditions. We also wish to repo0rt our
preliminary results on the cyclization of ortho-[1 -aza-
cycloalkyl]benzaldehydes in water in the presence of a base
or in dry media, using Al2O3–KF as basic solid support.
Microwave(MW)-assisted solvent-free reactions have
received much attention due to their enhanced reaction
rates as well as higher yields and purities. These methods
are regarded as environmentally benign and easy-to-per-
form, paving the way to the development of ‘Green
Chemistry’ protocols.1 Such kind of transformations can
be conveniently and rapidly carried out in open vials,
without having the problem of boiling solvents and
excessive pressure build-up. In addition to their practical
interest, MW-assisted solvent-free reactions, performed
neat or on a non-absorbing support, are highly suitable to
study the possible occurrence of special non-thermal MW
effects,2–4 as the absorption of the radiation is limited to the
reactive species and not masked by any absorption of the
solvent (essentially important when polar solvents are
concerned). Recently, we reinvestigated the application of
the tert-amino effect for the synthesis of pyridopyridazines
and quinolines using MW irradiation.5 Significant rate
enhancements and yields, higher than those obtained under
conventional heating conditions (D), were observed.
However, in most cases, high boiling solvents were used,
hampering the isolation of the final compounds. In this
communication, we wish to report our recent study on the
2. Results and discussion
A strict comparison between reactions under MW
irradiation and conventional heating conditions has been
made, using a dedicated monomode MW reactor Discover
(CEM) and a pre-heated oil bath under the same set of
conditions. The bulk temperature of all reactions mixtures
was measured by infrared detection (for closed vessel
reactions, magnetical stirring, when using solvents) or by a
fiber optic temperature sensor (for open vessel reactions,
mechanical stirring, solvent-free conditions). The tempera-
ture profiles (ramp and hold time) appeared to be nearly
identical under both MW and conventional heating
conditions, avoiding thus any effect of thermal inertia.
Temperature/power profile is given in one typical example
(Fig. 1).
Two series of starting materials 1a–c, and 3a–c, synthesized
according to the procedures described earlier,6–8 were
heated neat above their melting points under both
conventional heating and MW irradiation conditions9
Keywords: Microwave; tert-Amino effect; Pyrido-fused; Solvent free.
*
Corresponding author. Tel.: C32 16 327406; fax: C32 1 2170851;
e-mail: erik.vandereycken@chem.kuleuven.ac.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.046

N. Kaval et al. / Tetrahedron 61 (2005) 9052–9057
9053
vinyl-tert-aniline 1a provided the fused product 2a in 99%
yield under both MW and conventional heating conditions,
whereas in solution the isolated yields never exceeded 80%.
Analogous results were obtained for the compound 1b.
Using the solvent-free procedure, the dinitrile derivative 3a
underwent ring closure in 18 min under MW irradiation
(Fig. 1) and in 20 min under conventional heating
conditions to afford the desired product 4a in 75 and 78%
yield, respectively. It should be noted that the best yield for
the corresponding reaction in solution was 35% (DMSO,
150 8C, 44 h). However, when the reaction time was
increased to 20 min, the yield of MW-assisted experiment
dropped to 67% and turned out to be lower than the one
obtained under oil bath conditions (78%) due to partial
decomposition of the compounds. The dimethylbarbituric
acid derivative 3b has been cyclized under both MW-
assisted and conventional solvent-free conditions at 210 8C
within 1 min to afford the expected spirocyclic system 4b in
almost quantitative yield, compared to only 63% under the
best conditions in n-butanol under MW irradiation.5
Figure 1. Temperature/power profile for the microwave-assisted solvent-
free cyclization of 3a in sealed vessel; temperature control using feedback
from IR thermography (200 8C ceiling temperature, 200 W maximum
power, 2 min ramp time, 18 min hold time).
On the contrary, conventional heating or MW irradiation of
the Meldrum’s acid derivative 3c at its melting point
resulted in decomposition of the starting material, which can
probably be explained by an easy decarboxylation of 3c at
this elevated temperature. The above-mentioned problem
could be partially avoided by performing the reaction at
175 8C on neutral alumina, providing the spirocyclic
product 4c in 31% yield under conventional heating
conditions and in 55% yield for the MW-assisted reaction,
next to decomposition. The isolated yields appeared to be
lower than the ones reported for the reactions in solution,
but we could perform the cyclization in a substantially
shorter time (7 min vs 5 h or 30 min) following this safe and
Scheme 1. Solid-phase synthesis of pyrido-fused heterocycles.
(Scheme 1). In comparison with the reactions in solution,7,8
the solvent-free procedure furnishes a remarkable improve-
ment in yields and purities of the obtained products
(Table 1). Thus, solvent-free cyclization of the ortho-
Table 1. Synthesis of pyrido-fused systems
Compound; mp (8C)
Solution-phase reactionsa
Solvent-free reactionsb
Method of
activation
Solvent
Temp (8C)/
timec
Yield of 2 or 4
(%)
Method of
activation
Temp (8C)/
time (min)
Yield of 2 or 4
(%)
D
MW
D
n-BuOH
n-BuOH
n-BuOH
n-BuOH
117/2 h
200/3 min
117/22 h
78
80
67
73
D
MW
D
MW
D
150/5
150/5
170/17
170/17
180/22
180/5
99
99
87
86
94
!2
94
58d
57e
78
75
67
97
96
0 g
31
0 g
55
1a (122)
1b (88)
MW
220/15 min
D
n-BuOH
n-BuOH
DMSO
DMSO
117/ 35 h
220/30 min
150/44 h
84
96
35
29
D
1c (133–138 decomp.)
MW
MW
D
180/22
180/5
MW
D
200/18
200/20
200/18
200/20
210/1
210/1
216/1
175/ 7
216/1
175/7
D
3a (180)
3b (209)
3c (216)
MW
MW
D
MW
210/42 min
D
MW
xylenef
n-BuOH
138/2 h
230/5 min
45
63
MW
D
Dh
D
DMF
DME
100/5 h
79
73
MW
MWh
MW
200/30 min
a Results reported in the literature.5,7,8
b All reactions were carried out in open vessels on a 0.5 mmol scale, for MW-assisted experiments at a maximum power level of 300 W for 1a–c, 3b–c and at
200 W for 3a.
c Hold time for MW-assisted experiments.
d Ratio 1c:2cZ1:1.7 determined by GC and 1H NMR.
e Ratio 3a:4aZ1:9 determined by GC and 1H NMR.
f
Performed with a catalytic amount of aluminum trichloride.
g Only decomposition of the starting material was observed.
h Performed on neutral alumina.

9054
N. Kaval et al. / Tetrahedron 61 (2005) 9052–9057
environmentally friendly protocol. For all solvent-free
conversions, except for the dinitrile derivative 3a, the
yields as well as the time needed to reach completion
appeared to be more or less the same under both
conventional heating and MW irradiation conditions.
When the morpholine derivative 1c was heated neat at
180 8C for 22 min, the fused compound 2c was formed in
94% yield in both MW and oil bath experiments. However,
when the same reactions were checked after 5 min,
practically no conversion of starting material 1c was
observed under conventional heating conditions, whereas
MW irradiation seemed to be superior, providing the
cyclized product 2c in 58% yield.
substituted with a thiocarbonyl group in the ortho-
position,12 has already been described in the literature.
However, because of the better stabilization of the negative
charge in the resonance form 6 (Scheme 2), in order to allow
the intramolecular [1.5] hydrogen shift, a strongly electron-
withdrawing group adjacent to the carbonyl moiety (RZ
CF3) or a thiocarbonyl group (XZS) were reported to be
crucial for this reaction to take place.11a,12
Here, we report our further investigations concerning the
formation of benz-1,3-oxazines under microwave
irradiation. First we examined the activity of aldehyde 9a
toward cyclization (Scheme 3). According to our previously
reported procedure,5 an aqueous suspension of 9a was
irradiated at 200 8C for 60 min in the presence of K2CO3
(1 equiv) to give benzoxazine 10a in 41% yield together
with 28% of recovered starting material (Table 2, entry 1)
(caution: irradiation of the reaction mixture at a ceiling
temperature above 200 8C, resulted in a rapid increase of
pressure). Irradiation of an aqueous suspension of aldehyde
9a at a lower temperature or for a shorter time, resulted in
lower yields of benzoxazine 10a. Moreover, performing the
reaction applying the same set of parameters, but under
conventional heating, did not result in any conversion of
starting material (entry 2). Without the addition of base the
reaction did not proceed neither in polar solvents (n-butanol
or water, entries 4 and 5), nor when aldehyde 9a was heated
neat at a ceiling temperature of 200 8C (entry 6).
Surprisingly, irradiation of a solution of 9a in n-butanol in
the presence of 1 equiv of K2CO3 resulted in formation of
alcohol 11a, together with unreacted starting material (entry
3). This could point to the occurrence of a competitive
Cannizzaro reaction, although we were unable to detect the
corresponding carboxylic acid. Lewis acid catalysis with
AlCl3 or TFA seemed to be ineffective (entries 7 and 8).
Surprisingly the benz-1,3-oxazine 10a was obtained in 17%
yield when silica was used as a solid support (entry 9). In
order to gain insight in the reaction mechanism, the
irradiation of a suspension of aldehyde 9a in D2O in the
presence of K2CO3 (1 equiv) was carried out under the same
In the course of our investigations of the ‘tert-amino effect’
under MW irradiation we reported the formation of benz-1,
3-oxazines10 by ring closure of benzaldehydes bearing a
N,N-dialkylamino group in the ortho-position.5 The prep-
aration of such benz-1,3-oxazines, starting from ortho-acyl-
N,N-dialkylanilines11 or 1-(1-pyrrolidinyl)-benzenes
Scheme 2. Proposed mechanism for the cyclization of 5.11a,12
Scheme 3. Cyclization of benzaldehyde derivatives 9a–f.
Table 2. Cyclization of 2-(pyrrolidin-1-yl)benzaldehyde 9a
Entry
Activation mode
Conditionsa
Product (yield, %)
1
2
3
4
5
6
7
8
MW
D
H2O, K2CO3 (1 equiv), 90 W, 200 8C, 60 min
H2O, K2CO3 (1 equiv), 200 8C, 60 min
n-BuOH, K2CO3 (1 equiv), 300 W, 200 8C, 60 min
n-BuOH, 300 W, 250 8C, 60 min
10a (41%) 9a (28%)
—
b
MW
MW
MW
MW
MW
MW
MW
MW
MW
D
11ac
—
b
b
H2O, 300 W, 194 8Cd, 60 min
—
b
Neat, 300 W, 200 8C, 60 min
—
b
Toluene, AlCl3 (cat), 300 W, 200 8C, 30 min
H2O, TFA (1 equiv), 150 W, 200 8C, 30 min
Silicaf 100 W, 200 8C, 60 min
—
—
e
9
10a (17%)
10a(41%)g
10a(42%)
10a (28%)
10
11
12
13
D2O, K2CO3 (1 equiv), 90 W, 200 8C, 60 min
Al2O3–KF (3:1)h, 100 W, 200 8C, 60 min
Al2O3–KF (3:1)h, 200 8C, 60 min
i
e
—
MW
Al2O3 , 100 W, 200 8C, 60 min
a All reactions were performed on a 1 mmol scale in closed vessels with pressure control all along the reaction.
b No reaction, only starting material was recovered.
c Determined by CI-MS, not isolated.
d This is the maximum temperature that the system could reach.
e Complex mixture.
f
0.3 g of silica gel/mmol of starting material.
g No D insertion was observed.
h 0.4 g of Al2O3–KF/mmol of starting material.
i
0.3 g of Al2O3/mmol of starting material.

N. Kaval et al. / Tetrahedron 61 (2005) 9052–9057
9055
conditions as for entry 1 (entry 10). No incorporation of
deuterium in the obtained benz-1,3-oxazine 10a was
observed, supporting the concept of a concerted cyclization
mechanism (Scheme 2).11a
investigated the cyclization of ortho-(10-azacycloalkyl)
benzaldehydes to benz-1,3-oxazines in water in the presence
of base or in dry media using Al2O3–KF as a basic solid-
support under both conventional and MW-assisted con-
ditions. The ring size of the tert-amino substituent seems to
play an important role for the outcome of this reaction.
In order to develop a solvent free protocol, on the way to
‘Green Chemistry’, we decided to investigate the appli-
cation of a basic solid support. Alumina/KF, introduced by
Clark and Ando13 seemed to be interesting for this purpose.
This support differs from other oxide-type solid base
catalysts due to so-called ‘half-naked’ and thus active
fluorine anions, making it especially effective in promoting
various base-catalyzed reactions.14
4. Experimental
4.1. General
Melting points were determined using a Reichert-Jung
Thermovar apparatus or an Electrothermal 9200 digital
melting point apparatus, and are uncorrected. 1H NMR
spectra were recorded on a Bruker WM 250 or Bruker
Avance 300 instrument, using CDCl3 as solvent. The 1H and
13C chemical shifts are determined in ppm relative to
tetramethylsilane, or using the residual solvent signal as an
internal reference. Mass spectra were recorded by using a
Kratos MS50TC and a Kratos Mach III data system. The ion
source temperature was 150–250 8C as required. For thin-
layer chromatography, analytical TLC plates (Alugram SIL
G/UV254 and 70–230 mesh silicagel (E.M. Merck)) were
used. Crude products were analyzed by gas chromatography
(GC 9000 Series Fisions), which was fitted with a non-polar
capillary column and a Turbochrom data system developed
by Perkin Elmer Co. Semiempirical (PM3) calculations
were carried out by using Spartan program package (Spartan
SGI Version 5.1.1., Wavefunction Inc. 1998) on silicon
graphics (INDY R 4400). All chemicals were purchased
from the commercial sources (across) and used without
further purification. Aluminum oxide (basic, particle size
0.05–0.15 mm) was purchased from Fluka. Compounds
1a–c, 3a–c and 9a–f were prepared according to the
published procedures.6–8 Compounds 2a–c and 4a–c have
melting points and spectral data identical with the published
values.7,8 Compound 11e is available from commercial
sources (CAS N 465514-33-4).
To get a proper dispersion of aldehyde 9a on the support, the
compound was dissolved in 0.5 mL of dichloromethane,
which was subsequently evaporated from the alumina/KF
suspension, under reduced pressure. The resulting solid was
heated at 200 8C for 60 min under either MW-assisted or
conventional conditions (entries 11 and 12) to provide benz-
1,3-oxazine 10a in 42 and 28% yield, respectively.
It should be noted that the use of basic alumina without KF
(entry 13) resulted in the formation of a complex mixture
containing only traces of the desired compound. To evaluate
the scope and limitations of this method, a set of ortho-[10-
azacycloalkyl]benzaldehydes6 was submitted to the
optimized reaction conditions. Aqueous suspensions of
aldehydes 9b–f were irradiated at 200 8 C for 60 min in the
presence of K2CO3 (1 equiv) or aldehydes 9b–f were
dispersed on an Al2O3–KF (3:1) mixture and irradiated at
200 8C for 60 min. Unfortunately only in the case of 9b
acceptable yields were obtained (Table 3). Switching from a
five-membered pyrolidine substituent to a six-membered
piperidine or morpholine moiety seems to have a deleterious
effect on the outcome of this ring closure. Remarkably, an
attempt to cyclize aldehydes 9e,f in aqueous media resulted
in the formation of the alcohols 11e,f, without any trace of
the desired compounds, whereas irradiation of 9e,f on
Al2O3–KF, afforded the benzoxazines 10e,f.
4.2. Microwave irradiation experiments
3. Conclusion
A monomode CEM-Discover MW reactor (CEM Corpo-
ration PO Box 200 Matthews, NC 28106) was used in the
standard configuration as delivered, including proprietary
software.15 All experiments were carried out in MW process
vials (10 mL) with control of the temperature by infrared
detection or fiber optic temperature sensor for open vessel
experiments (as was the case for the reactions performed
under conventional heating conditions). After completion of
the reaction, the vial was cooled to 50 8C via air jet cooling.
A new operationally simple, safe and environmentally
benign solvent-free procedure is described for the synthesis
of different pyridopyridazines and quinolines, applying the
tert-amino effect under both MW and conventional heating
conditions. The isolated yields of the solvent-free reactions
appeared to be significantly higher than the ones obtained in
the corresponding reactions in solution. We also
Table 3. Cyclization of ortho-(10-azacycloalkyl)benzaldehydes 9b–f (Scheme 3)a
Entry
Aldehyde
R
n
X
Products (yield, %)
In waterb
On Al2O3–KFc
1
2
3
4
5
9b
9c
9d
9e
9f
MeO
H
MeO
H
MeO
0
1
1
1
1
CH2
CH2
CH2
O
10b (51) 9b (11)
10c (14) 9c (30)
10d (14) 9d (27)
11e (10) 9e (69)
11f (16) 9f (50)
10b (52) 9b (5)
10c (9) 9c (19)
10d (9) 9d (17)
10e (6) 9e (17)
10f (6) 9f (10)
O
a All reactions were performed on a 1 mmol scale; according to TLC-analysis, besides decomposition, no other compounds were formed than the one indicated.
b H2O, K2CO3(1 equiv), 90 W, 200 8C, 60 min.
c Al2O3/KF (3:1), 0.4 g/mmol of starting material, 100 W, 200 8C, 60 min.

9056
N. Kaval et al. / Tetrahedron 61 (2005) 9052–9057
4.3. Solvent-free cyclization of 3c on aluminum oxide
(d, 1H, JZ14.6 Hz), 4.85 (d, 1H, JZ14.6 Hz), 4.32 (dd, 1H,
3JZ8, 3.7 Hz), 3.69 (m, 1H), 2.72 (m, 1H), 2.03 (m, 1H),
1.75 (m, 4H), 1.50 (m, 1H). 13C NMR (CDCl3): 146.0,
127.8, 125.0, 124.2, 120.1, 115.7, 86.5, 67.9, 47.3, 31.8,
25.6, 21.8. DEPT (CDCl3): 127.8, 125.0, 120.1, 115.7, 86.5,
K67.9, K47.3, K31.8, K25.6, K21.8. MS (CI): m/z (%)Z
190 (100) [MHC]. HR-MS (EI): C12H15ON calcd
189.11536, found 189.11484.
Neutral alumina (0.8 g) was added to a solution of 3c
(0.17 g, 0.5 mmol) in dichloromethane (1 mL) and the
solvent was evaporated under reduced pressure. The
resulting yellowish powder was transferred to a vial and
heated in an oil bath at 175 8C for 7 min or irradiated at
175 8C for 7 min (hold time) at 300 W maximum power.
The vial was cooled to room temperature, the crude mixture
was transferred to the top of a column filled with silica gel
and purified using dichloromethane–ethylacetate (1:9) as
eluent to give an analytically pure sample of 4c in 55%
yield.
4.4.4. 8-Methoxy-2,3,4,4a-tetrahydro-1H,6H-pyrido-
[1,2-a][3,1]benzoxazine (10d). H NMR (CDCl3): d 6.90
1
3
4
(d, 1H, JZ8.8 Hz), 6.76 (dd, 1H, JZ8.8 Hz, JZ2.9 Hz),
6.50 (d, 1H, JZ2.9 Hz), 4.99 (d, 1H, JZ14.6 Hz), 4.84 (d,
1H, JZ14.6 Hz), 4.31 (q, 1H, JZ2.9 Hz), 3.76 (s, 3H), 3.45
(m, 1H), 2.78 (m, 1H), 1.97 (m, 1H), 1.76 (m, 4H), 1.51 (m,
1H). 13C NMR (CDCl3): 154.4, 140.5, 126.5, 119.4, 113.7,
110.0, 86.3, 67.9, 55.9, 48.9, 31.4, 25.7, 20.9. DEPT
(CDCl3): 119.4, 113.7, 110.0, 86.3, K67.9, 55.9, K48.9,
K31.4, K25.7, K20.9. MS (CI): m/z (%)Z220 (100)
[MHC]. HR-MS (EI): C13H17O2N calcd 219.12593, found
219.12549.
4.4. Typical procedures for MW-assisted cyclizations of
ortho-(10-azacyclo-alkyl)benzaldehydes
(A). In water. A suspension of aldehyde 9a–f (1 mmol) and
K2CO3 (1 mmol) in water (3 mL) was irradiated in closed
vessels with pressure control at 200 8C for 60 min (hold
time) at 90 W maximum power. The reaction mixture was
extracted with dichloromethane (10 mL!3). The combined
organic layers were dried over Mg2SO4, filtered and
evaporated. The residue was subjected to column chroma-
tography on silica gel (eluent: dichloromethane–hexanes
1:1) for compounds 10a–c or dichloromethane for
compounds 10d–f, 11e,f to afford benzoxazines 10a–f and
alcohols 11e,f as oils.
4.4.5. 1,2,4,4a-Tetrahydro-6H-[1,4]oxazino[4,3-a][3,1]-
1
benzoxazine (10e). H NMR (CDCl3): d 7.20 (t, 1H, JZ
7.3 Hz), 6.89 (m, 3H), 5.05 (d, 1H, JZ14.6 Hz), 4.90 (d,
3
1H, JZ14.6 Hz), 4.37 (dd, 1H, JZ7, 3.6 Hz), 3.99 (m,
2H), 3.66 (m, 2H), 3.18 (t, 1H, JZ5.1 Hz), 2.96 (m, 1H).
MS (CI): m/z (%)Z192 (100) [MHC]. HR-MS (EI):
C11H13O2 calcd 191.09463, found 191.09509.
(B). On alumina. A solution of aldehyde 9a–f (1 mmol) in
dichloromethane (0.5 mL) was added to a mixture of
Al2O3–KF (0.4 g, 3:1 w/w) and the solvent was evaporated
under reduced pressure. The resulting yellowish powder
was irradiated at 200 8C for 60 min at 100 W power, cooled
to room temperature, applied on the top of a column with
silica gel and purified as indicated under (A).
4.4.6. 8-Methoxy-1,2,4,4a-tetrahydro-6H-[1,4]oxazino-
[4,3-a][3,1]benzoxazine (10f). H NMR (CDCl3): d 6.87
1
3
4
(d, 1H, JZ8.8 Hz), 6.76 (dd, 1H, JZ8.8 Hz, JZ2.9 Hz),
6.53 (d, 1H, JZ2.9 Hz), 5.02 (d, 1H, JZ14.6 Hz), 4.90 (d,
1H, JZ14.6 Hz), 4.29 (q, 1H, JZ2.9 Hz), 3.91 (m, 4H),
3.77 (s, 3H), 3.42 (m, 1H), 2.93 (m, 1H). 13C NMR (CDCl3):
155.0, 139.6, 126.5, 119.6, 113.9, 110.1, 82.9, 69.4, 67.7,
67.3, 55.9, 48.1. DEPT (CDCl3): 119.6, 113.9, 110.1, 82.9,
K69.4, K67.7, K67.3, 55.9, K48.1. MS (CI): m/z (%)Z
222 (100) [MHC].
4.4.1. 1,2,3,3a-Tetrahydro-5H-pyrrolo[1,2-a][3,1]benz-
oxazine (10a). 1H NMR (CDCl3): d 7.16 (t, 1H, JZ
7.3 Hz), 6.93 (d, 1H, JZ7.3 Hz), 6.75 (t, 1H, JZ7.3 Hz),
6.71 (d, 1H, JZ8 Hz), 4.96 (d, 1H, JZ14.6 Hz), 4.95 (m,
1H), 4.77 (d, 1H, JZ14.6 Hz), 3.62 (m, 1H), 3.27 (m, 1H),
2.35 (m, 1H), 2.01 (m, 3H). 13C NMR (CDCl3): 143.6,
128.1, 125.1, 122.0, 118.3, 115.6, 89.9, 68.6, 50.1, 32.8,
23.0. DEPT (CDCl3): 128.1, 125.1, 118.3, 115.6, 89.9,
K68.6, K50.1, K32.8, K23.0. MS (CI): m/z (%)Z176
(100) [MHC]. HR-MS (EI): C11H13ON calcd 175.09971,
found 175.09869.
4.4.7. (2-Morpholinophenyl)methanol (11e). 1H NMR
(CDCl3): d 7.23 (m, 4H), 4.98 (br s, 1H), 4.83 (s, 2H), 3.89
(t, 4H, JZ4.4 Hz), 3.01 (t, 4H, JZ4.4 Hz). 13C NMR
(CDCl3): 150.9, 136.0, 129.2, 128.9, 125.5, 121.1, 67.9,
64.8, 53.2. DEPT (CDCl3): 129.2, 128.9, 125.5, 121.1,
K67.9, K64.8, K53.2. MS (CI): m/z (%)Z194 (26)
[MHC], 176 (31) [MHCKH2O].
4.4.2. 7-Methoxy-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]
[3,1]benzoxazine (10b). H NMR (CDCl3): d 6.76 (d, 2H,
1
JZ1.5 Hz), 6.52 (s, 1H), 4.90 (d, 1H, JZ14.6 Hz), 4.87 (m,
1H), 4.73 (d, 1H, JZ14.6 Hz), 3.76 (s, 3H), 3.59 (m, 1H),
3.17 (m, 1H), 2.33 (m, 1H), 1.99 (m, 3H). 13C NMR
(CDCl3): 153.4, 133.7, 124.3, 119.1, 114.1, 110.4, 90.1,
68.2, 56.1, 51.9, 32.9, 23.2. DEPT (CDCl3): 119.1, 114.1,
110.4, 90.1, K68.2, 56.1, K51.9, K32.9, K23.2. MS (CI):
m/z (%)Z206 (100) [MHC]. HR-MS (EI): C12H15O2N
calcd 205.11028, found 205.10572.
4.4.8. (5-Methoxy-2-morpholinophenyl)methanol (11f).
1H NMR (CDCl3): d 7.17 (d, 1H, JZ8.1 Hz), 6.82 (dd, 1H,
4
3JZ8.1 Hz, JZ2.9 Hz), 6.75 (d, 1H, JZ2.9 Hz), 4.78 (s,
2H), 3.86 (t, 4H, JZ4.4 Hz), 3.80 (s, 3H), 2.94 (t, 4H, JZ
4.4 Hz). 13C NMR (CDCl3): 157.4, 143.9, 137.6, 122.6,
114.3, 113.6, 67.9, 65.1, 55.8, 53.6. DEPT (CDCl3): 122.6,
114.3, 113.6, K67.9, K65.1, 55.8, K53.6. MS (CI): m/z
(%)Z224 (62) [MHC], 206 (31) [MHCKH2O], 194 (6)
[MHCKMe2O]. HR-MS (EI): C12H17O3N calcd
223.12084, found 223.12110.
4.4.3. 2,3,4,4a-Tetrahydro-1H,6H-pyrido[1,2-a][3,1]-
1
benzoxazine (10c). H NMR (CDCl3): d 7.17 (t, 1H, JZ
7.3 Hz), 6.93 (d, 2H, JZ8 Hz), 6.85 (t, 1H, JZ7.3 Hz), 5.02

N. Kaval et al. / Tetrahedron 61 (2005) 9052–9057
9057
´
8. (a) Matyus, P.; Fuji, K.; Tanaka, K. Heterocycles 1994, 37,
¨
171–174. (b) Schwartz, A; Beke, G.; Kovari, Z.; Bocskey, Z.;
Acknowledgements
´
¨
Farkas, O. ; Matyus, P. J. Mol. Struct. (Theochem) 2000, 528,
´
´
49–57. (c) Beke, G.; Gergely, A.; Szasz, G.; Szentesi, A.;
N. K. and E. V. d. E. wish to thank the F.W.O. (Fund for
Scientific Research—Flanders (Belgium)) and the Research
Fund of the Katholieke Universiteit Leuven for financial
support to the laboratory. N. K., E. V. d. E., G. V. T. and A. L.
are gratefulfor financial support via a Tournesol-Egide project
T2004.14, and N. K. wishes to thank the French Embassy in
Belgium for obtaining a scholarship for a 1 month stay in
France. P.M. thanks for financial supports provided by ETT
(121/2003), OTKA (047328) and NKTH-RET (Szentagothai
Knowledge Centre). The CEM company is acknowledged
(A. L.) for putting a Discover equipment at our disposal.
´ ´
Nyitray, J.; Barabas, O.; Harmath, V.; Matyus, P. Chirality
2002, 14, 365–371.
9. The slope of the melting profile of polar species is dramatically
increased under MW irradiation compared to conventional
heating conditions (D), showing an inflection point around
their melting point.
10. The formation of benz-1,3-oxazines was for the first time
described by Kienzle, F. Tetrahedron Lett. 1983, 24,
2213–2216.
11. (a) Verboom, W.; van Dijk, B. G.; Reinhoudt, D. N.
Tetrahedron Lett. 1983, 24, 3923–3926. (b) Okada, V.; Otsuki,
Y.; Shinohara, M.; Medebielle, M.; Shimizu, Y.; Takeuchi, H.
Tetrahedron Lett. 2003, 44, 741–743. (c) Okada, V.; Tsukushi,
N.; Otsuki, Y.; Nishiyama, S.; Fukuda, T. Synlett 1999,
126–128. (d) Okada, E.; Masuda, R.; Hojo, M.; Tonifuji, T.
Heterocycles 1993, 36, 845–856. (e) Hojo, M.; Masuda, R.;
Okada, E. Tetrahedron Lett. 1988, 29, 4599–4602.
12. Verboom, W.; Hamzink, M. R. J.; Reinhoudt, D. N.; Visser, R.
Tetrahedron Lett. 1984, 38, 4309–4312.
References and notes
1. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault,
´
P.; Mathe, D. Synthesis 1998, 1213–1234.
2. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9225.
(b) Perreux, L.; Loupy, A. Microwaves in Organic Synthesis.
E; Wiley-VCH: Weinheim, 2002.
13. (a) Clark, H. Chem. Rev. 1980, 39, 429–452. (b) Ando, T.;
Yamawaki, Y. Synth. Org. Chem. Jpn. 1981, 39, 14–24.
14. Kabashima, H.; Tsuji, H.; Nakota, Sh.; Tanaka, Y.; Hattori, H.
Appl. Catal. A: Gen. 2000, 194–195 pp 227–240, and
references cited therein.
3. Loupy, A. C.R. Chimie 2004, 7, 103–112.
´
´
4. Loupy, A.; Maurel, F.; Sabatie-Gogova, A. Tetrahedron 2004,
60, 1683–1691.
5. Kaval, N.; Dehaen, W.; Matyus, P.; Van der Eycken, E. Green
´
Chem. 2004, 6, 125–127.
6. Niewiadomski, B.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1975, 1679–1682.
15. Discover, CEM Corporation, P.O. Box 200 Matthews, NC
28106. For a detailed description of the monomode MW
apparatus, see: Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001,
3, 624–630.
7. Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S.
J. Org. Chem 1984, 49, 269–276.